Nothing more dramatically captures the imagination of the visually impaired patient or the ophthalmologist treating them than the possibility of rebuilding a damaged retina with "stem cells." Defined as pluripotent cells capable of differentiating into a variety of cell types, stem cells can be derived from early embryos or adults and, under appropriate conditions, will differentiate into a variety of tissues. Stem cells have been identified in cord blood and adult bone marrow and represent a pool of progenitor cells that may serve to provide cells that maintain various tissue types as well as rescue/repair damaged tissue following injury or stress. These adult stem cells may have wide utility in the treatment of retinal vascular diseases and even inherited retinal degenerations. While the use of these cells to target neovasculature and contribute to the stabilization of otherwise friable vessels in ischemic retinopathies may seem intuitive, an associated neurotrophic effect observed recently (Otani, et al, 2004) is surprising but reasonable given newly emerging paradigms describing the existence of trophic "cross-talk" between local vascular networks and the tissues they supply. Thus, potential applications of these cells includes not only cell based therapeutic delivery of various trophic and static substances, but also as stabilizing elements in an otherwise unstable neovasculature of the type observed in ischemic retinopathies. In this proposal we will apply emerging technologies in stem cell biology, gene therapy, proteomics, large scale genomic analysis and live cell imaging to develop stem cell-based therapies for the treatment of vascular and degenerative diseases of the retina. This will be accomplished by (1) identifying and isolating a fraction of progenitor cells from adult bone marrow and cord blood that will target diseased vasculature in the retina and exert trophic rescue effects in animal models of retinal vascular and degenerative disease;(2) determining the mechanism whereby these trophic effects are achieved;(3) engineering a process for the preparation and characterization of the functional cell fraction;and (4) conducting the necessary pre-clinical pharmacological, toxicological and pharmacokinetic studies to take this approach into the clinics. If successful, these studies will lead to a novel therapeutic paradigm for currently untreatable vascular and degenerative diseases of the retina.